Method of making implantable medical devices having controlled surface properties

ABSTRACT

An implantable medical device that is fabricated from materials that present a blood or body fluid or tissue contact surface that has controlled heterogeneities in material constitution. An endoluminal stent-graft and web-stent that is made of a monolithic material formed into differentiated regions defining structural members and web regions extending across interstitial spaces between the structural members. The endoluminal stent-graft is characterized by having controlled heterogeneities at the blood flow surface of the stent.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of and commonly ownedapplication Ser. No. 13/168,865, filed Jun. 24, 2011, now U.S. Pat. No.10,092,390, issued Oct. 9, 2018, which is a continuation of applicationSer. No. 12/652,582, filed Jan. 5, 2010, now U.S. Pat. No. 8,715,335,issued May 6, 2014, which is a continuation of application Ser. No.10/289,843 filed Nov. 6, 2002, now U.S. Pat. No. 7,641,680, issued Jan.5, 2010, which is a continuation of application Ser. No. 09/532,164filed Mar. 20, 2000, now U.S. Pat. No. 6,537,310, issued Mar. 25, 2003,and which is a continuation-in-part of application Ser. No. 09/443,929filed Nov. 19, 1999, now U.S. Pat. No. 6,379,383, issued Apr. 30, 2002,each herein incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention pertains generally to implantable medical devicesand, more particularly, to implantable medical devices which are capableof being implanted utilizing minimally-invasive delivery techniques.More particularly, the present invention relates to endoluminal grafts,stent-grafts and stent-graft-type devices that are implanted intoanatomical passageways using minimally invasive delivery techniques.More specifically, the present invention comprises endoluminal grafts,stent-grafts and stent-graft-type devices that are fabricated entirelyof biocompatible metals or of biocompatible materials which exhibitbiological response and material characteristics substantially the sameas biocompatible metals, such as for example composite materials.

Conventional endoluminal stents and stent-grafts are frequently usedpost-angioplasty in order to provide a structural support for a bloodvessel and reduce the incidence of restenosis following percutaneousballoon angioplasty. A principal example of the present invention areendovascular stents which are introduced to a site of disease or traumawithin the body's vasculature from an introductory location remote fromthe disease or trauma site using an introductory catheter, passedthrough the vasculature communicating between the remote introductorylocation and the disease or trauma site, and released from theintroductory catheter at the disease or trauma site to maintain patencyof the blood vessel at the site of disease or trauma. Stent-grafts aredelivered and deployed under similar circumstances and are utilized tomaintain patency of an anatomic passageway, for example, by reducingrestenosis following angioplasty, or when used to exclude an aneurysm,such as in aortic aneurysm exclusion applications.

While the use of endoluminal stents has successfully decreased the rateof restenosis in angioplasty patients, it has been found that asignificant restenosis rate continues to exist even with the use ofendoluminal stents. It is generally believed that the post-stentingrestenosis rate is due, in major part, to a failure of the endotheliallayer to regrow over the stent and the incidence of smooth musclecell-related neointimal growth on the luminal surfaces of the stent.Injury to the endothelium, the natural nonthrombogenic lining of thearterial lumen, is a significant factor contributing to restenosis atthe situs of a stent. Endothelial loss exposes thrombogenic arterialwall proteins, which, along with the generally thrombogenic nature ofmany prosthetic materials, such as stainless steel, titanium, tantalum,Nitinol, etc. customarily used in manufacturing stents, initiatesplatelet deposition and activation of the coagulation cascade, whichresults in thrombus formation, ranging from partial covering of theluminal surface of the stent to an occlusive thrombus. Additionally,endothelial loss at the site of the stent has been implicated in thedevelopment of neointimal hyperplasia at the stent situs. Accordingly,rapid re-endothelialization of the arterial wall with concomitantendothelialization of the body fluid or blood contacting surfaces of theimplanted device is considered critical for maintaining vasculaturepatency and preventing low-flow thrombosis.

At present, most endoluminal stents are manufactured of stainless steel,which is known to be thrombogenic. In order to reduce thethrombogenicity of the stainless steel and to maintain sufficientdimensional profiles for catheter delivery, most stents minimize themetal surface area that contacts blood, in order to minimize thrombusformation after implantation. Thus, in order to reduce the thrombogenicresponse to stent implantation, as well as reduce the formation ofneointimal hyperplasia, it would be advantageous to increase the rate atwhich endothelial cells form endothelium proximal and distal to thestent situs, migrate onto and provide endothelial coverage of theluminal surface of the stent which is in contact with blood flow throughthe vasculature.

Stent-grafts are essentially endoluminal stents with a discrete coveringon either or both of the luminal and abluminal surfaces of the stentthat occludes the open spaces, or interstices, between adjacentstructural members of the endoluminal stent. It is known in the art tofabricate stent-grafts by covering the stent with endogenous vein or asynthetic material, such as woven polyester known as DACRON, or withexpanded polytetrafluoroethylene. Additionally, it is known in the artto cover the stent with a biological material, such as a xenograft orcollagen. A primary purpose for covering stents with grafts is to reducethe thrombogenic effect of the stent material. However, conventionalgrafts are not a complete solution to enhancing the healing response ofthe devices.

Heretofore, the art has not provided 1) a graft fabricated ofbiocompatible metals or of biocompatible materials which exhibit in vivobiological and mechanical responses substantially the same asbiocompatible metals (hereinafter referred to as “metal-likematerials”); 2) a stent-graft device in which a structural component, orstent, and a graft component are each fabricated of metal or metal-likematerials; and 3) a stent-graft-type device in which a structuralsupport, such as a stent, defines openings which are subtended by a web,with both the stent and the web being formed as a single, integral,monolithic structure and fabricated of metals or of metal-likematerials, this particular embodiment is hereinafter referred to as a“web-stent.”

SUMMARY OF THE INVENTION

Graft Embodiment

As used herein the term “Graft” is intended to indicate any type oftubular member which exhibits integral columnar and circumferentialstrength and which has openings which pass through the thickness of thetubular member.

In accordance with a preferred embodiment of the invention, a graftmember is formed as a discrete thin sheet or tube of biocompatiblemetals or metal-like material. A plurality of openings is provided whichpass transversely through the graft member. The plurality of openingsmay be random or may be patterned. It is preferable that the size ofeach of the plurality of openings be such as to permit cellularmigration through each opening, without permitting fluid flow therethrough. In this manner, blood cannot flow through the plurality ofopenings, but various cells or proteins may freely pass through theplurality of openings to promote graft healing in vivo. In accordancewith another aspect of the inventive graft embodiment, it iscontemplated that two graft members are employed, with an outer diameterof a first graft member being smaller than the inner diameter of asecond graft member, such that the first graft member is concentricallyengageable within a lumen of the second graft member. Both the first andsecond graft members have a pattern of a plurality of openings passingthere through. The first and second graft members are positionedconcentrically with respect to one another, with the plurality ofpatterned openings being positioned out of phase relative to one anothersuch as to create a tortuous cellular migration pathway through the wallof the concentrically engaged first and second graft members. In orderto facilitate cellular migration through and healing of the first andsecond graft members in vivo, it is preferable to provide additionalcellular migration pathways that communicate between the plurality ofopenings in the first and second graft members. These additionalcellular migration pathways may be imparted as 1) a plurality ofprojections formed on either the luminal surface of the second graft orthe abluminal surface of the first graft, or both, which serve asspacers and act to maintain an annular opening between the first andsecond graft members that permits cellular migration and cellularcommunication between the plurality of openings in the first and secondgraft members, or 2) a plurality of microgrooves, which may be random,radial, helical, or longitudinal relative to the longitudinal axis ofthe first and second graft members, the plurality of microgrooves beingof a sufficient size to permit cellular migration and propagation alongthe groove without permitting fluid flow there through, the microgroovesserve as cellular migration conduits between the plurality of openingsin the first and second graft members.

Stent-Graft Embodiment

In accordance with another preferred embodiment of the presentinvention, a graft member may be formed as either a thin sheet ofmaterial or as a tubular member, and mechanically joined to cover aplurality of structural support members. The graft member may be used tocover either a luminal or abluminal surface, or both, of an endoluminaldevice.

A stent-graft in accordance with the present invention may be formed byconjoining a discrete graft member with a plurality of structuralsupport members, such as a stent, by mechanically joining the graftmember to regions of the plurality of structural support members.Alternatively, a stent-graft may be formed by first forming, such as byvacuum deposition methods or by etching a pre-existing material blank, agraft member as a contiguous thin sheet or tube which projects outwardlyfrom at least one aspect of the plurality of structural members. Thethin sheet is then everted over the structural members and brought intoa position adjacent a terminal portion of the plurality of structuralmembers such that it covers one or both of the putative luminal orabluminal surfaces of the plurality of structural members. The graftmember is then mechanically joined at an opposing end, i.e., theputative proximal or the putative distal end of the plurality ofstructural members.

The stent-graft is formed entirely of a metal or metal-like material,which, as opposed to using conventional synthetic polymeric graftmaterials, the inventive graft material exhibits improved healingresponse.

Web-Stent Embodiment

In accordance with one of the embodiments of the present invention,there is provided a stent-graft-type device, termed a “web-stent” inwhich there is at least one of a plurality of structural members thatprovide a primary means of structural support for the webbed-stentdevice. The plurality of structural members may be arranged in anymanner as is known in the art of stent fabrication, e.g., single elementforming a circle or ellipse, a single or plural elements which form atubular diamond-like or undulating pattern, in which adjacent structuralmembers are spaced apart forming open regions or interstices betweenadjacent structural members. In the present invention, the intersticesor open regions between adjacent structural members are subtended by aweb of material that is the same material or a material exhibitingsimilar biological and mechanical response as the material that formsthe plurality of structural members. The web may be formed within all ora portion of the interstitial area or open regions between the pluralityof structural support members.

Method of Making Graft, Stent-Graft and Web-Stent

Finally, the present invention provides a method of fabricating thegraft, stent-graft and web-stent devices of the present invention. Theinventive method consists of forming the device by vacuum deposition ofa film, either as a planar sheet or as a tube, of a biocompatiblematerial, such as nickel-titanium alloys. The thickness of the depositedmaterial is determined by the particular embodiment being fabricated.After the deposited film is created, either additive or subtractivemethodologies are employed to define: the structural members, theinterstitial web regions, the graft regions and/or a plurality ofopenings through the deposited film. Alternatively, a pre-fabricatedstarting film of a biocompatible material, such as Nitinol, may beemployed, and the stent-pattern formed by vacuum deposition methods orby conventional metal forming techniques, or by removing regions of thepre-fabricated film to form the interstitial regions of the web-stentdevice.

Where a graft member is being fabricated, the thickness of the depositedor pre-fabricated starting film may be less than that where a web-stentis being formed, due to the absence of structural members in the graftmember. However, where a stent-graft or a web-stent is being fabricated,structural members may be formed by alternative methods. The structuralmembers may be formed by additive techniques by applying a pattern ofstructural members onto a film, such as by vacuum deposition techniquesor conventional metal forming techniques, such as laminating or casting.Second, subtractive or selective removal techniques may be employed toremove material from patterned regions on a film, such as by etching apattern of interstitial regions between adjacent structural membersuntil a thinner film is created which forms the web subtending theplurality of structural members. Where a pre-existing stent is employedas the structural members, obviously, the structural members do not needto be fabricated or formed.

In accordance with the best mode contemplated for the present invention,the graft, the plurality of structural members and the web arefabricated of the same or similar metals or metal-like materials. Inorder to improve healing response, it is preferable that the materialsemployed have substantially homogenous surface profiles at the blood ortissue contact surfaces thereof. A substantially homogeneous surfaceprofile is achieved by controlling heterogeneities along the blood ortissue-contacting surface of the material. The heterogeneities that arecontrolled in accordance with an embodiment of the present inventioninclude: grain size, grain phase, grain material composition,stent-material composition, and surface topography at the blood flowsurface of the stent. Additionally, the present invention providesmethods of making endoluminal devices having controlled heterogeneitiesin the device material along the blood flow or tissue-contacting surfaceof the device. Material heterogeneities are preferably controlled byusing conventional methods of vacuum deposition of materials onto asubstrate.

The surface of a solid, homogeneous material can be conceptualized ashaving unsaturated inter-atomic and intermolecular bonds forming areactive plane ready to interact with the environment. In practice, aperfectly clean surface is unattainable because of immediate adsorptionof airborne species, upon exposure to ambient air, of O, O₂, CO₂, SO₂,NO, hydrocarbons and other more complex reactive molecules. Reactionwith oxygen implies the formation of oxides on a metal surface, aself-limiting process, known as passivation. An oxidized surface is alsoreactive with air, by adsorbing simple, organic airborne compounds.Assuming the existence of bulk material of homogeneous subsurface andsurface composition, oxygen and hydrocarbons may adsorb homogeneously.Therefore, further exposure to another environment, such as the vascularcompartment, may be followed by a uniform biological response.

Current metallic vascular devices, such as stents, are made from bulkmetals made by conventional methods, and stent precursors, such ashypotubes, are made by many steps that introduce processing aides to themetals. For example, olefins trapped by cold drawing and transformedinto carbides or elemental carbon deposit by heat treatment, typicallyyield large carbon rich areas in 316L stainless steel tubingmanufactured by cold drawing process. The conventional stents havemarked surface and subsurface heterogeneity resulting from manufacturingprocesses (friction material transfer from tooling, inclusion oflubricants, chemical segregation from heat treatments). This results information of surface and subsurface inclusions with chemical compositionand, therefore, reactivity different from the bulk material. Oxidation,organic contamination, water and electrolytic interaction, proteinadsorption and cellular interaction may, therefore, be altered on thesurface of such inclusion spots. Unpredictable distribution ofinclusions such as those mentioned above provide an unpredictable anduncontrolled heterogeneous surface available for interaction with plasmaproteins and cells. Specifically, these inclusions interrupt the regulardistribution pattern of surface free energy and electrostatic charges onthe metal surface that determine the nature and extent of plasma proteininteraction. Plasma proteins deposit nonspecifically on surfacesaccording to their relative affinity for polar or non-polar areas andtheir concentration in blood. A replacement process known as the Vromaneffect, Vroman L., The importance of surfaces in contact phasereactions, Seminars of Thrombosis and Hemostasis 1987; 13(1): 79-85,determines a time-dependent sequential replacement of predominantproteins at an artificial surface, starting with albumin, following withIgG, fibrinogen and ending with high molecular weight kininogen. Despitethis variability in surface adsorption specificity, some of the adsorbedproteins have receptors available for cell attachment and thereforeconstitute adhesive sites. Examples are: fibrinogen glycoproteinreceptor IIbIIIa for platelets and fibronectin RGD sequence for manyblood activated cells. Since the coverage of an artificial surface withendothelial cells is a favorable end-point in the healing process,favoring endothelialization in device design is desirable in implantablevascular device manufacturing.

Normally, endothelial cells (EC) migrate and proliferate to coverdenuded areas until confluence is achieved. Migration, quantitativelymore important than proliferation, proceeds under normal blood flowroughly at a rate of 25 μm/hr or 2.5 times the diameter of an EC, whichis nominally 10 μm. EC migrate by a rolling motion of the cell membrane,coordinated by a complex system of intracellular filaments attached toclusters of cell membrane integrin receptors, specifically focal contactpoints. The integrins within the focal contact sites are expressedaccording to complex signaling mechanisms and eventually couple tospecific amino acid sequences in substrate adhesion molecules (such asRGD, mentioned above). An EC has roughly 16-22% of its cell surfacerepresented by integrin clusters. Davies, P. F., Robotewskyi A., GriemM. L. Endothelial cell adhesion in real time. J. Clin. Invest. 1993;91:2640-2652, Davies, P. F., Robotewski, A., Griem, M. L., Qualitativestudies of endothelial cell adhesion, J. Clin. Invest. 1994;93:2031-2038. This is a dynamic process, which implies more than 50%remodeling in 30 minutes. The focal adhesion contacts vary in size anddistribution, but 80% of them measure less than 6 μm2, with the majorityof them being about 1 μm², and tend to elongate in the direction of flowand concentrate at leading edges of the cell. Although the process ofrecognition and signaling to determine specific attachment receptorresponse to attachment sites is incompletely understood, regularavailability of attachment sites, more likely than not, would favorablyinfluence attachment and migration. Irregular or unpredictabledistribution of attachment sites, that might occur as a result ofvarious inclusions, with spacing equal or smaller to one whole celllength, is likely to determine alternating hostile and favorableattachment conditions along the path of a migrating cell. Theseconditions may vary from optimal attachment force and migration speed toinsufficient holding strength to sustain attachment, resulting in cellslough under arterial flow conditions. Due to present manufacturingprocesses, current implantable vascular devices exhibit such variabilityin surface composition as determined by surface sensitive techniquessuch as atomic force microscopy, X-ray photoelectron spectroscopy andtime-of-flight secondary ion mass spectroscopy.

There have been numerous attempts to increase endothelialization ofimplanted stents, including covering the stent with a polymeric material(U.S. Pat. No. 5,897,911), imparting a diamond-like carbon coating ontothe stent (U.S. Pat. No. 5,725,573), covalently binding hydrophobicmoieties to a heparin molecule (U.S. Pat. No. 5,955,588), coating astent with a layer of blue to black zirconium oxide or zirconium nitride(U.S. Pat. No. 5,649,951), coating a stent with a layer of turbostraticcarbon (U.S. Pat. No. 5,387,247), coating the tissue-contacting surfaceof a stent with a thin layer of a Group VB metal (U.S. Pat. No.5,607,463), imparting a porous coating of titanium or of a titaniumalloy, such as Ti—Nb—Zr alloy, onto the surface of a stent (U.S. Pat.No. 5,690,670), coating the stent, under ultrasonic conditions, with asynthetic or biological, active or inactive agent, such as heparin,endothelium derived growth factor, vascular growth factors, silicone,polyurethane, or polytetrafluoroethylene, U.S. Pat. No. 5,891,507),coating a stent with a silane compound with vinyl functionality, thenforming a graft polymer by polymerization with the vinyl groups of thesilane compound (U.S. Pat. No. 5,782,908), grafting monomers, oligomersor polymers onto the surface of a stent using infrared radiation,microwave radiation or high voltage polymerization to impart theproperty of the monomer, oligomer or polymer to the stent (U.S. Pat. No.5,932,299).

Thus, the problems of thrombogenicity and re-endothelializationassociated with stents have been addressed by the art in various mannerswhich cover the stent with either a biologically active or an inactivecovering which is less thrombogenic than the stent material and/or whichhas an increased capacity for promoting re-endothelialization of thestent situs. These solutions, however, all require the use of existingstents as substrates for surface derivatization or modification, andeach of the solutions result in a biased or laminate structure builtupon the stent substrate. These prior art coated stents are susceptibleto delaminating and/or cracking of the coating when mechanical stressesof transluminal catheter delivery and/or radial expansion in vivo.Moreover, because these prior art stents employ coatings applied tostents fabricated in accordance with conventional stent formationtechniques, e.g., cold-forming metals, the underlying stent substrate ischaracterized by uncontrolled heterogeneities on the surface thereof.Thus, coatings merely are laid upon the heterogeneous stent surface, andinherently conform to the topographical heterogeneities in the stentsurface and mirror these heterogeneities at the blood contact surface ofthe resulting coating. This is conceptually similar to adding a coat offresh paint over an old coating of blistered paint; the fresh coatingwill conform to the blistering and eventually, blister and delaminatefrom the underlying substrate. Thus, topographical heterogeneities aretypically telegraphed through a surface coating. Chemicalheterogeneities, on the other hand, may not be telegraphed through asurface coating but may be exposed due to cracking or peeling of theadherent layer, depending upon the particular chemical heterogeneity.

The current invention entails creating materials specifically designedfor manufacture of grafts, stents, stent-grafts and other endoluminaldevices. According to a preferred embodiment of the invention, themanufacture of grafts, stents, stent-grafts and other endoluminaldevices is controlled to attain a regular, homogeneous atomic andmolecular pattern of distribution along their surface. This avoids themarked variations in surface composition, creating predictable oxidationand organic adsorption patterns and has predictable interactions withwater, electrolytes, proteins and cells. Particularly, EC migration issupported by a homogeneous distribution of binding domains that serve asnatural or implanted cell attachment sites, in order to promoteunimpeded migration and attachment. Based on observed EC attachmentmechanisms such binding domains should have a repeating pattern alongthe blood contact surface of no less than 1 μm radius and 2 μmborder-to-border spacing between binding domains. Ideally, theinter-binding domain spacing is less than the nominal diameter of anendothelial cell in order to ensure that at any given time, a portion ofan endothelial cell is in proximity to a binding domain.

In accordance with the present invention, there is provided a web-stentdevice in which there is at least one of a plurality of structuralmembers that provides a primary means of structural support for theweb-stent device. The plurality of structural members is spaced apart toform open regions or interstices between adjacent structural members. Inthe present invention, a web of material, that is the same or similar tothe material which forms the plurality of structural members, subtendsthe interstices or open regions between adjacent structural members. Theweb may be formed within all or a portion of the interstitial area oropen regions between the plurality of structural support members. Boththe plurality of interconnected structural members and the web may beformed of initially substantially planar materials or of initiallysubstantially cylindrical materials.

In accordance with another preferred embodiment of the presentinvention, there is provided a stent-graft device in which a graftmember is formed as a film of material and mechanically joined to one orboth of the proximal and distal ends of the plurality of structuralsupport members, and covers that surface of the plurality of structuralsupport members which is to form either the luminal or abluminal surfaceof the stent-graft device. The graft member may be formed eitherseparately or as a contiguous thin-film projecting from the plurality ofstructural members. Where the graft member is formed as a contiguousthin-film projecting from the plurality of structural members, the thinfilm is either abluminally everted or luminally inverted and broughtinto a position adjacent to the plurality of structural members suchthat it covers either, or both, the luminal or abluminal surfaces or theplurality of structural members, then is attached at an opposing end,i.e., the putative proximal or the putative distal end of the pluralityof structural members.

In accordance with another embodiment of the invention, there isprovided a graft formed as a discrete thin sheet or tube ofbiocompatible metal or metal-like materials. A plurality of openings isprovided which pass transversely through the graft member. The pluralityof openings may be random or may be patterned. It is preferable that thesize of each of the plurality of openings be such as to permit cellularmigration through each opening, without permitting fluid flow therethrough. In this manner, blood cannot flow through the plurality ofopenings, but various cells or proteins may freely pass through theplurality of openings to promote graft healing in vivo.

In accordance with another aspect of the inventive graft embodiment, itis contemplated that two graft members are employed, with an outerdiameter of a first graft member being smaller than the an innerdiameter of a second graft member, such that the first graft member isconcentrically engageable within a lumen of the second graft member.Both the first and second graft members have a plurality of patternedopenings passing there through. The first and second graft members arepositioned concentrically with respect to one another, with theplurality of patterned openings being positioned out of phase relativeto one another such as to create a tortuous cellular migration pathwaythrough the wall of the concentrically engaged first and second graftmembers. In order to facilitate cellular migration and healing of thefirst and second graft members, it is preferable to provide additionalcellular migration pathways that communicate between the plurality ofopenings in the first and second graft members. These additionalcellular migration pathways may be imparted as 1) a plurality ofprojections formed on either the luminal surface of the second graft orthe abluminal surface of the first graft, or both, which serve asspacers and act to maintain an annular opening between the first andsecond graft members and permit cellular migration in order tocommunicate between the plurality of openings in the first and secondgraft members, or 2) a plurality of microgrooves, which may be random,radial, helical, or longitudinal relative to the longitudinal axis ofthe first and second graft members, the plurality of microgrooves beingof a sufficient size to permit cellular migration and propagation alongthe groove without permitting fluid flow there through, the microgroovesserve as cellular migration conduits between the plurality of openingsin the first and second graft members.

The present invention also provides a method of fabricating theweb-stent device which entails providing a planar or tubular film of abiocompatible material, such as forming the film by vacuum deposition,then removing interstitial regions until a thinner film region iscreated which forms a web subtending a plurality of structural members.Alternatively, a pre-existing conventionally produced sheet or tube of abiocompatible material, such as Nitinol, may be etched until a thinnerfilm is created in the etched regions, thereby forming the interstitialweb areas of the web-stent device.

Finally, in accordance with the present invention, there is provided animplantable endoluminal device that is fabricated from materials thatpresent a blood or tissue contact surface that is substantiallyhomogeneous in material constitution. More particularly, the presentinvention provides an endoluminal graft, stent, stent-graft andweb-stent that is made of a material having controlled heterogeneitiesalong the blood flow or tissue-contacting surface of the stent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a photographic top plan view of a web-stent in accordance withthe present invention.

FIG. 2 is a perspective view of a preferred embodiment of the web-stentof the present invention.

FIG. 3 is a perspective view of a stent-graft in accordance with thepresent invention.

FIG. 4 is a perspective view of an alternative embodiment of theinventive stent-graft.

FIG. 5 is a cross-sectional view taken along line 5-5 of FIG. 4.

FIG. 6 is a cross-sectional view illustrating a pair of support membersand a section of interstitial web between adjacent supporting members.

FIG. 7 is a cross-sectional view illustrating a pair of support membersand a section of interstitial web between adjacent supporting members inaccordance with an alternative embodiment of the present invention.

FIG. 8A is a top plan view of a graft or web region with a plurality ofopenings passing there through.

FIG. 8B is a top plan view of an alternative embodiment of a graft orweb region of the present invention with a plurality of openings passingthere through.

FIG. 8C is a top plan view of a third embodiment of a graft or webregion of the present invention with a plurality of openings passingthere through.

FIG. 9A is a transverse cross-sectional view of a first embodiment of agraft member in accordance with the present invention.

FIG. 9B is a transverse cross-sectional view of a second embodiment of agraft member in accordance with the present invention.

FIG. 10 is a flow chart diagrammatically illustrating the method offabricating the graft, stent-graft and/or web-stent of the presentinvention.

FIG. 11 is a diagrammatic representation of controlled heterogeneitiesin a surface of the inventive implantable medical device.

FIG. 12 is a micrograph of uncontrolled heterogeneities present in priorart stent material.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the present invention, stent, web-stent and stent-graftdevices are provided which preferably exhibit substantially homogenoussurface properties. The inventive graft, stent, stent-graft andweb-stent devices may be made utilizing a pre-fabricated film or adeposited film, either in a planar or cylindrical conformation, theneither adding a pattern of support members to the film or removing atleast some regions of the film to create thinner regions in the startingfilm and defining relatively thinner and thicker film regions, such asthinner web regions between adjacent structural members formed bythicker film regions and/or relatively thinner graft regions. Anadditive methodology may include vacuum deposition or lamination of apattern of support members upon the planar or cylindrical film. Asubtractive methodology includes etching unwanted regions of material bymasking regions to form the structural members and expose unmaskedregions to the etchant. Additionally, in order to improve in vivohealing, it is advantageous to impart openings passing through the webor the graft. The openings are preferably produced during the process offorming the web or the graft. The openings in the web or the graft maybe formed by conventional methods such as photolithographic processes,by masking and etching techniques, by mechanical means, such as laserablation, EDM, or micromachining, etc. Suitable depositionmethodologies, as are known in the microelectronic and vacuum coatingfabrication arts and incorporated herein by reference, are plasmadeposition and physical vapor deposition which are utilized to impart ametal layer onto the stent pattern.

In accordance with an aspect of the present invention there is provideda vacuum deposited device that is fabricated of a material havingsubstantially homogeneous surface properties across the blood contactsurface of the device. Current manufacturing methods for fabricatingendoluminal stents fail to achieve the desired material properties ofthe present invention. As discussed above, stents are fabricated frombulk metals that are processed in a manner that incorporates processingaides to the base metal. Presently, stents are made from hypotubesformed from bulk metals, by machining a series of slots or patterns intothe hyptotube to accommodate radial expansion, or by weaving wires intoa mesh pattern.

The present invention consists of a stent made of a bulk material havingcontrolled heterogeneities on the luminal surface thereof.Heterogeneities are controlled by fabricating the bulk material of thestent to have defined grain sizes that yield areas or sites along thesurface of the stent having optimal protein binding capability. Thecharacteristically desirable properties of the inventive stent are: (a)optimum mechanical properties consistent with or exceeding regulatoryapproval criteria, (b) controlling discontinuities, such as cracking orpinholes, (c) a fatigue life of 400 MM cycles as measured by simulatedaccelerated testing, (d) corrosion resistance, (e) biocompatibilitywithout having biologically significant impurities in the material, (f)a substantially non-frictional abluminal surface to facilitateatraumatic vascular crossing and tracking and compatible withtranscatheter techniques for stent introduction, (g) radiopaque atselected sites and MRI compatible, (h) have a luminal surface which isoptimized for surface energy and microtopography, (i) minimalmanufacturing and material cost consistent with achieving the desiredmaterial properties, and (j) high process yields.

Controlling the surface profile of an endoluminal device is significantbecause blood protein interactions with surfaces of endoluminal devicesappear to be the initial step in a chain of events leading to tissueincorporation of the endovascular device. The present invention isbased, in part, upon the relationship between surface energy of thematerial used to make the endoluminal device and protein adsorption atthe surface of the endoluminal device. The present inventors have foundthat a relationship exists between surface free energy and proteinadsorption on metals commonly used in fabrication of endoluminaldevices. In addition, specific electrostatic forces resident on thesurface of metal endoluminal stents have been found to influence bloodinteractions with the stent surface and the vascular wall.

In accordance with a preferred embodiment the present invention, theinventive grafts, stent-grafts and web-stents have surface profileswhich are achieved by fabricating the graft, stent-graft and web-stentby the same metal deposition methodologies as are used and standard inthe microelectronic and nano-fabrication vacuum coating arts, and whichare hereby incorporated by reference. In accordance with a preferredembodiment the present invention, the preferred deposition methodologiesinclude ion-beam assisted evaporative deposition and sputteringtechniques. In ion beam-assisted evaporative deposition it is preferableto employ dual and simultaneous thermal electron beam evaporation withsimultaneous ion bombardment of the material being deposited using aninert gas, such as argon, xenon, nitrogen or neon. Bombardment withinert gas ions during deposition serves to reduce void content byincreasing the atomic packing density in the deposited material. Thereduced void content in the deposited material allows the mechanicalproperties of that deposited material to be similar to the bulk materialproperties. Deposition rates up to 20 nm/sec are achievable using ionbeam-assisted evaporative deposition techniques.

When sputtering techniques are employed, a 200-micron thick stainlesssteel film may be deposited within about four hours of deposition time.With the sputtering technique, it is preferable to employ a cylindricalsputtering target, a single circumferential source that concentricallysurrounds the substrate that is held in a coaxial position within thesource.

Alternate deposition processes which may be employed to form the stentin accordance with the present invention are cathodic arc, laserablation, and direct ion beam deposition. As known in the metalfabrication arts, the crystalline structure of the deposited filmaffects the mechanical properties of the deposited film. Thesemechanical properties of the deposited film may be modified bypost-process treatment, such as by, for example, annealing.

Materials to make the inventive graft, stent-graft and web-stent arechosen for their biocompatibility, mechanical properties, i.e., tensilestrength, yield strength, and their ease of deposition include, withoutlimitation, the following: elemental titanium, vanadium, aluminum,nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium,niobium, scandium, platinum, cobalt, palladium, manganese, molybdenumand alloys thereof, such as zirconium-titanium-tantalum alloys, nitinol,and stainless steel.

During deposition, the chamber pressure, the deposition pressure and thepartial pressure of the process gases are controlled to optimizedeposition of the desired species onto the substrate. As is known in themicroelectronic fabrication, nano-fabrication and vacuum coating arts,both the reactive and non-reactive gases are controlled and the inert ornon-reactive gaseous species introduced into the deposition chamber aretypically argon and nitrogen. The substrate may be either stationary ormoveable; either rotated about its longitudinal axis, moved in an X-Yplane, planatarily or rotationally moved within the deposition chamberto facilitate deposition or patterning of the deposited material ontothe substrate. The deposited material maybe deposited either as auniform solid film onto the substrate, or patterned by (a) impartingeither a positive or negative pattern onto the substrate, such as byetching or photolithography techniques applied to the substrate surfaceto create a positive or negative image of the desired pattern or (b)using a mask or set of masks which are either stationary or moveablerelative to the substrate to define the pattern applied to thesubstrate. Patterning may be employed to achieve complex finishedgeometries of the resultant structural supports, web-regions or graft,both in the context of spatial orientation of patterns of regions ofrelative thickness and thinness, such as by varying the thickness of thefilm over its length to impart different mechanical characteristicsunder different delivery, deployment or in vivo environmentalconditions.

The device may be removed from the substrate after device formation byany of a variety of methods. For example, the substrate may be removedby chemical means, such as etching or dissolution, by ablation, bymachining or by ultrasonic energy. Alternatively, a sacrificial layer ofa material, such as carbon, aluminum or organic based materials, such asphotoresists, may be deposited intermediate the substrate and the stentand the sacrificial layer removed by melting, chemical means, ablation,machining or other suitable means to free the stent from the substrate.

The resulting device may then be subjected to post-deposition processingto modify the crystalline structure, such as by annealing, or to modifythe surface topography, such as by etching to expose a heterogeneoussurface of the device.

Turning now to the Figures, there is illustrated alternative preferredembodiments of the present invention. In FIGS. 1 and 2 there isillustrated a web-stent 20 in accordance with the present invention. Theweb-stent 20 is formed of a material blank 10, which has been eitherpre-manufactured or has been vacuum deposited as a planar or cylindricalfilm. The web-stent 20 is formed by masking regions of the materialblank which are to form a plurality of structural members 22, and thenetching the unmasked regions which then form interstitial webs 24 whichsubtend interstitial regions between adjacent structural members 22. Theinterstitial webs 24 are etched to a material thickness that is lessthan the thickness of the plurality of structural members 22. It ispreferable to impart a plurality of openings in the interstitial webs 24in order to permit endothelialization of the luminal surface 26 of theinterstitial webs 24. The openings may be imparted as a random patternor as a regular pattern in the interstitial web 24, as will be discussedhereinafter.

With reference to FIG. 3 there is depicted a stent-graft 30 inaccordance with the present invention. Stent-graft 30 is formed eitherfrom a tubular or planar material blank, which is etched to form theplurality of structural members 32 and interstitial regions 34 betweenthe structural members 32. In addition, either or both a proximal 36 ora distal 38 graft region of the stent are provided and project outwardlyfrom terminal structural members 32. The proximal graft region 36 andthe distal graft region 38 are preferably etched to a reduced thicknessof less than the thickness of the structural members, and are made withopenings passing there through which promote cellular migration, as willbe discussed hereinafter.

Under certain applications it may be useful to employ the stent-graft 30with either or both of the proximal 36 or distal 38 graft regionsprojecting outwardly from the structural supports 32. An alternativeembodiment of the invention is illustrated in FIGS. 4 and 5. Thealternative embodiment of the stent-graft 30 involves covering theluminal and abluminal surfaces of a plurality of structural supports 32with a luminal graft 36 and an abluminal graft 38. The luminal graft 36may initially be formed as the proximal graft region 36 in FIG. 3 and beluminally inverted 39 and passed into the lumen defined by thestructural members 32. The abluminal graft 38 may initially be formed asthe distal graft region 38 in FIG. 3 and be abluminally everted 37 overthe structural members 32. Alternatively, the luminal graft 36 and theabluminal graft 38 may be formed as either pre-fabricated discrete graftmembers made of biocompatible metal or metal-like materials that areeither tubular or planar then formed into a tube and concentricallyengaged about the plurality of structural members 32. Portions of eachof the abluminal graft 38 and the luminal graft 36 are mechanicallyjoined to the plurality of structural members 32 or to one and other,thereby effectively encapsulating the plurality of structural members 32between the luminal graft 36 and the abluminal graft 38. It ispreferable that opposing free ends of each of the abluminal graft 38 andluminal graft 36 are mechanically joined to and co-terminus with aterminal portion of the plurality of structural members 32. Mechanicaljoining may be accomplished by methods such as welding, suturing,adhesive bonding, soldering, thermobonding, riveting, crimping, ordovetailing. In accordance with an alternate embodiment of theinvention, the interstitial regions 34 may be subtended by a web 34, asdiscussed hereinabove, with reference to FIGS. 1 and 2.

Those of ordinary skill in the art, will understand and appreciate thatalternative methods of removing material from areas that form relativelythinner regions of the stent, web-stent or stent-graft may be employed.For example, in addition to chemical etching, relatively thinner regionsmay be formed by removing bulk material by ion milling, laser ablation,EDM, laser machine, electron beam lithography, reactive ion etching,sputtering or equivalent methods which are capable of reducing thethickness of the material in either the graft region or the interstitialweb region between the structural members. Alternatively, the structuralmembers may be added to the defined interstitial web or graft regions toform the device, or the interstitial web or graft regions may be addedto pre-existing structural members. Additive methods that may beemployed include conventional metal forming techniques, includinglaminating, plating, or casting.

Similarly, a wide variety of initial bulk material configurations may beemployed, including a substantially planar sheet substrate, an arcuatesubstrate or a tubular substrate, which is then processed by eithersubtractive or additive techniques discussed above.

By forming the structural members, the interstitial web and/or the graftof an integral, monolithic material, both the circumferential or hoopstrength of the resultant device, as well as the longitudinal orcolumnar strength of the device are enhanced over conventionalstent-graft devices. Additional advantages of the present invention,depending upon fabrication methods, may include: controlled homogeneityand/or heterogeneity of the material used to form the device bydeposition methodologies, enhanced ability to control dimensional andmechanical characteristics of the device, the ability to fabricatecomplex device conformations, ability to pattern and control theporosity of the web and/or graft regions, and a monolithic one-piececonstruction of a device which yields a minimized device profile andcross-sectional area. The devices of the present invention haverelatively thicker and thinner regions, in which the thinner regionspermit radial collapse of the device for endoluminal delivery. Theinventive device exhibits superior column strength that permits smallerintroducer size and more readily facilitates deployment of the device.

As illustrated in FIGS. 6 and 7, the web and/or graft regions, 44, 54between adjacent structural members 42, 52 may be co-planar with eitherthe luminal or abluminal surface of the structural members 42, or may bepositioned intermediate the luminal 51 and abluminal 56 surfaces of thestructural members 52.

In accordance with a preferred embodiment of the present invention, theweb regions of the inventive web-stent, the graft regions of theinventive stent-graft and the inventive graft have a plurality ofopenings which pass through the thickness of the material used tofabricate the inventive devices. Each of the plurality of openings isdimensioned to permit cellular migration through the opening withoutpermitting blood leakage or seepage through the plurality of openings.The plurality of openings may be random or may be patterned. However, inorder to control the effective porosity of the device, it is desirableto impart a pattern of openings in the material used to fabricate theinventive device.

FIGS. 8A-8C depict several examples of patterned openings in a sectionof material used to make the inventive web-stent, graft regions of thestent-graft, and the inventive graft. FIG. 8A depicts a material 60 witha plurality of circular openings 64 passing through the materialsubstrate 62. The plurality of circular openings is patterned in aregular array of rows and columns with regular inter-opening spacing 65between adjacent openings. In the particular embodiment illustrated thediameter of each of the plurality of openings is about 19 μm, with aninter-opening spacing in each row and column of about 34 μm on center.The thickness of the material 62 is approximately 10 μm. FIG. 8Billustrates another example of a pattern of a plurality of openingsuseful in the present invention. The material 62, which again isapproximately 10 μm in thickness, has a plurality of openings 66 and 67passing there through. The pattern of the plurality of openings 66 and67 is an alternating slot pattern in which the plurality of openings 66are arrayed adjacent one and other forming a y-axis oriented array 68relative to the material 62, while a plurality of openings 67 arearrayed adjacent one and other forming an x-axis oriented array 69relative to the material 62. The y-axis-oriented array 68 and thex-axis-oriented array 69 are then positioned adjacent one and other inthe material 62. In this particular example, the inter-array spacingbetween the y-axis-oriented array 68 and the x-axis-oriented array 69 isabout 17 μm, while each of the plurality of openings has a length ofabout 153 μm and a width of about 17 μm. Finally, FIG. 8C illustrates amaterial 60 in which the material substrate 62 has a regular array of aplurality of diamond-shaped openings 63 passing through the materialsubstrate 62. As with the alternative embodiments exemplified in FIGS.8A and 8B, the dimension of the plurality of diamond-shaped openings 63is of sufficient size to permit cellular migration through the openings63, while preventing blood flow or seepage through the plurality ofopenings 63.

FIGS. 9A and 9B illustrate alternate preferred embodiments of the graft70 and graft 80 in accordance with the present invention. Graft 70consists generally of concentrically positioned luminal graft member 74and abluminal graft member 72 and an interfacial region 74 where theluminal surface of the abluminal graft member 72 and the abluminalsurface of the luminal graft member 74 are in immediate juxtapositionwith one and other. Both the luminal 74 and the abluminal 72 graftmembers are fabricated in accordance with the methodologies describedabove, and are provided with a plurality of patterned openings 73 in theabluminal graft member 72 and a plurality of patterned openings 75 inthe luminal graft member 74. The plurality of patterned openings 74 and75 are positioned out of phase relative to one another. By positioningthe plurality of patterned openings 74 and 75 in an out-of-phaserelationship, there is no continuous opening that passes through theinterfacial region 76 which would permit blood flow or seepage from thelumen of the graft. However, in order to permit cellular migration fromthe abluminal surface of the graft to the lumen of the graft, theinterfacial region 76 should have microroughness [not shown] which isoriented either randomly or selectively, such as helically orcircumferential, about the interfacial region 76. The microroughnesspreferably has a peak-to-valley depth of between about 5μ to about 65μ,most preferably between about 10μ to 15μ, may be either on the luminalsurface of the abluminal graft 72 or on the abluminal surface of theluminal graft 74, or both. The microroughness spans the surface arearegion between adjacent pairs of openings 74, 75, and the microroughnessdepth permits cellular migration across the surfaces between adjacentopenings 74 and 75. The microroughness is not large enough to permitfluid passage through the inter-opening regions at the interface betweenthe luminal graft 74 and the abluminal graft 72. This property ofpermitting cellular growth is similar to the difference between theporosity of expanded polytetrafluoroethylene grafts which do not requirepre-clotting, and the much larger porosity of polyester or DACRON graftswhich require pre-clotting to prevent fluid seepage there from.

FIG. 9B illustrates an alternative embodiment of the inventive graft 80in which an abluminal graft member 82 is concentrically positioned abouta luminal graft member 84. Each of the abluminal graft member 82 and theluminal graft member 84 having a plurality of patterned openings 83, 85,respectively, passing there through. As with the embodiment depicted inFIG. 9A, the plurality of patterned openings 83 and 85 are positioned inan out-of-phase relationship to one and other in order to preventforming a continuous opening between the luminal and abluminal surfacesof the graft 80. However, unlike the embodiment in FIG. 9A, there is nocorresponding interfacial region 74. Rather, an annular open region 87is positioned intermediate the luminal graft member 84 and the abluminalgraft member 82. The annular open region 87 is created by providing aplurality of microprojections 86 that project either radially inwardfrom the luminal surface of the abluminal graft member 82 or radiallyoutward from the abluminal surface of the luminal graft member 84. Theplurality of microprojections 86 act as spacers which abut the opposingsurface of either the luminal graft member 84 or the abluminal graftmember 82 which bound the annular open region 87. The height of themicroprojections 86 and, therefore, the size of the annular open region87, are dimensioned such that cells may migrate through the annular openregion 87, while blood flow or seepage will not occur between the lumenand the abluminal surface of the graft 80.

According to a specific aspect of the graft embodiment of the presentinvention, the size of the plurality of openings in the luminal graftmember 74, 84 may be different than the size of the plurality ofopenings in the abluminal graft member 72, 82. For example, theplurality of openings in the abluminal graft member 74, 84 preferablyhave a larger size than the plurality of openings in the luminal graftmember 72, 84, while still retaining the out-of-phase relationshipbetween the plurality of openings in the luminal 72, 82 and theabluminal 74, 84 graft members. Where circular openings are provided, itis preferable that the luminal 72, 82 and the abluminal 74, 84 graftmembers have openings having diameters of between about 5 μm and 100 μm.

Additionally, a third member may be interposed between the luminal 72,82 and the abluminal 82, 84 graft members. The third member willpreferably have a very fine plurality of openings, such as on the orderof between 2-10μ, and permits use of a higher porosity in the luminaland abluminal grafts, without the need to maintain an out-of-phaserelationship between the openings in the luminal 72, 82 and theabluminal 74, 84 graft members.

Finally, the method 90 for fabricating the inventive grafts,stent-grafts and web-stents of the invention is illustrated in theprocess flow diagram in FIG. 10. As previously discussed above, astarting blank of material may be formed either by providing apre-fabricated material blank of a biocompatible metal or metal-likematerial 92 or by vacuum depositing a starting blank of a biocompatiblemetal or metal like material film 94. Then a determination is madewhether to employ an additive or a subtractive method 96 for forming thegraft, stent-graft or web-stent. If an additive method is selected 97,the structural supports are built upon the starting blank 100, either byvacuum deposition techniques or by conventional metal formingtechniques. If a subtractive method is selected 95, the regions toremain are masked 98, then the unmasked regions are removed, such as bychemical etching or sputtering, to form the interstitial web regions,graft regions and/or openings in either the interstitial web regionsand/or graft regions 99.

The following examples are provided in order to illustrate thealternative embodiments of the invention, and are not intended to limitthe scope of the invention.

Example 1: Stent Formation by Sputtering

A ceramic cylindrical substrate is introduced into a deposition chamberwith capabilities of glow discharge substrate cleaning and sputterdeposition of carbon and stainless steel. The deposition chamber isevacuated to a pressure less than or equal to 2×10⁻⁷ Torr. Pre-cleaningof the substrate is conducted under vacuum by glow discharge. Thesubstrate temperature is controlled to achieve a temperature betweenabout 300 and 1100 degrees Centigrade. A bias voltage between −1000 and+1000 volts is applied to the substrate sufficient to cause energeticspecies arriving at the surface of the substrate to have hyperthermalenergy between 0.1 eV and about 700 eV, preferably between 5-50 eV. Thedeposition sources are circumferential and are oriented to deposit fromthe target circumferentially about the substrate.

During deposition, the deposition pressure is maintained between 0.1 and10 mTorr. A sacrificial carbon layer of substantially uniform thickness(□5%) between 10 and 500 Angstroms is deposited circumferentially on thesubstrate. After depositing the carbon layer, a cylindrical film ofstainless steel is deposited onto the sacrificial carbon layer on thecylindrical substrate at a deposition rate between about 10 to 100microns/hour. After formation of the stainless steel film, the substrateis removed from the deposition chamber and heated to volatilize theintermediate sacrificial carbon layer between the substrate and thefilm. After removing the carbon intermediate layer, the stainless steelfilm is removed from the substrate and exhibits material propertiessimilar to the bulk stainless steel target and surface propertiescharacterized by controlled heterogeneities in grain size, materialcomposition and surface topography. A series of patterns are thenmachined into the resultant stainless steel film to form a stent byelectrical discharge machining (EDM) or laser cutting the film.

Example 2: Stent Formation by Sputtering

The same operating conditions are followed as in Example 1, except thatthe substrate is tubular and selected to have a coefficient of thermalexpansion different than that of the resultant stent. No intermediatelayer of sacrificial carbon is deposited onto the substrate, and theouter surface of the substrate is etched with a pattern of recessesdefining a desired stent pattern. The substrate is mounted onto arotational jig within the deposition chamber and rotated at a uniformrate during deposition. Tantalum is used as the target material anddeposited into the recesses of the substrate from a single stationarysource. After deposition, the temperature of the substrate and thedeposited stent are controlled to impart diametric differential in thesubstrate and stent and permit removal of the stent from the substrate.

Example 3: Stent Formation by Ion Beam-Assisted Evaporative Deposition

A cylindrical substrate is introduced into a deposition chamber that hascapabilities of: substrate rotation and precise positioning, glowdischarge substrate cleaning, ion beam-assisted evaporative deposition,and cylindrical magnetron sputtering. The deposition sources are (a)dual electron beam evaporative sources placed adjacent to one another atthe base of the deposition chamber at a fixed distance from thesubstrate, these are used with simultaneous argon ion impingement ontothe substrate from a controlled ion beam source, and (b) a cylindricalmagnetron sputtering source with a carbon target capable ofcircumferentially coating a carbon sacrificial layer of substantiallyuniform thickness of between 10 and 200 Angstroms onto the substrate.

The substrate temperature is controlled to achieve a substratetemperature between about 300 and 1100 degrees Centigrade. Thedeposition chamber is evacuated to a pressure less than or equal to2×10⁻⁷ Torr. A pre-cleaning of the substrate is conducted under vacuumby glow discharge. The substrate is rotated to ensure uniform cleaningand subsequent uniform deposition thickness. After cleaning thesubstrate is moved into the magnetron and coated with the carbon layer.The substrate is then moved into position to receive the stent-formingmetal coating with simultaneous ion bombardment. One electron beamevaporation source contains titanium while the other source containsnickel. The evaporation rates of each of the titanium and nickelevaporation sources are separately controlled to form a nitinol alloy onthe substrate as the stent-forming metal.

Example 4: Planar Deposition of Stent

The same operating conditions of Example 3 are followed, except that aplanar substrate is used. The deposition source is a single electronbeam evaporation source containing platinum and is used withsimultaneous argon ion impingement onto the substrate from a controlledion beam source.

The substrate temperature is controlled to achieve a substratetemperature between about 300 and 1100 degrees Centigrade. Thedeposition chamber is evacuated to a pressure less than or equal to2×10⁻⁷ Torr. A pre-cleaning of the substrate is conducted under vacuumby glow discharge. After cleaning the substrate is moved into positionwithin the deposition chamber and coated with platinum from the electronbeam evaporation source with simultaneous argon ion bombardment, withthe electron beam evaporation source passing platinum through a patternmask corresponding to a stent pattern which is interposed between thesource and the substrate to pass a pattern of platinum onto thesubstrate.

After deposition, the patterned stent is removed from the substrate androlled about a forming substrate to a cylindrical shape and opposingends of the planar stent material are brought into juxtaposition withone another and may be attached by laser welding or left uncoupled.

Example 5: Thin-Film Deposition with Stent-Graft Etch

The same conditions are employed as in Example 4, except that a uniformlayer of stent-forming material is deposited having a thickness of 150microns without patterning of the stent onto the deposited layer.Rather, a negative mask is applied to the deposited stent-formingmaterial, and a chemical etchant is introduced to etch a pattern ofstructural elements into the stent-forming metal. The etchant ispermitted to react with the metal until a thinner film web having athickness of between 2-75 microns, is present between adjacentstructural elements. After the thinner film web is formed, the etchingis stopped, and the resultant stent-graft is removed and formed into atubular shape.

Example 6: Dry Etching Method

The same conditions as in Example 5 are followed, except that reactiveion etching is employed to form the thinner film web.

Example 7: Stent-Graft Formation

The same conditions are followed as in Example 5, except that thestructural elements are defined in an intermediate region of a tubularsubstrate, and interstitial regions between adjacent structural elementsare etched by chemical etching until interstitial openings are formedbetween adjacent structural elements while masking the structuralelements and proximal and distal regions of the tubular substrate.Proximal and distal graft regions are formed adjacent the intermediateregion of the tubular substrate and contiguous with the plurality ofstructural elements, by masking the structural elements and interstitialopenings and chemical etching the proximal and distal regions of thetubular substrate to yield a thinner film of material in the proximaland distal regions of the tubular substrate. The proximal and distalgraft regions are then everted, with the proximal graft region beinginverted luminally through the lumen of the structural members and thedistal graft region being everted abluminally over the structuralmembers. The proximal graft region is mechanically joined to the distalterminal end of the plurality of structural members, while the distalgraft region is mechanically joined to the proximal terminal end of theplurality of structural members, thereby encapsulating the plurality ofstructural members between the everted proximal and distal graftregions.

Example 8: Stent-Graft Formation—Discrete Graft and Discrete Stent

A pre-fabricated self-expanding superelastic shape memory alloy stent isprovided. Two cylindrical hypotubes of a superelastic shape memorymaterial similar to that of the stent are chemically etched to asubstantially uniform thickness of 10 □m, with a first hypotube havingan inner diameter which is of sufficient size to accommodate the outerdiameter of the stent, and a second hypotube having an outer diameterdimensioned to accommodate the inner diameter of the stent. The etchedhypotubes are then placed into a vacuum chamber and a cylindricalpattern mask having a regular array of circular openings, each circularopening having a diameter of about 25 μm, is positioned concentricallyabout each of the cylindrical hypotubes. The etched hypotubes arereactive ion etched to transfer the masked pattern to the etchedhypotube and impart a pattern of circular openings that pass through thewall thickness of the etched hypotubes corresponding to the maskpattern. The stent, and first and second etched and reactive ion etchedhypotubes are concentrically engaged upon one and other, with the secondhypotube being concentrically positioned within the lumen of the stentand the first hypotube being concentrically positioned about theabluminal surface of the stent. Proximal and distal ends of the stent,the first hypotube and the second hypotube are mechanically joined bywelding and then trimmed by laser cutting to ensure that the proximaland distal ends are co-terminus.

Example 9: Graft Formation

A cylindrical mandrel is provided which is coated with a sacrificiallayer. A plurality of patterned recesses is defined in the sacrificiallayer. The mandrel is introduced into a deposition chamber and anickel-titanium alloy is vacuum deposited onto the mandrel, whilerotating the mandrel, until a uniform adherent layer of the depositednickel-titanium alloy covers the cylindrical mandrel. After deposition,the sacrificial layer is removed, and the uniform adherent layerdisengaged from the cylindrical mandrel, yielding the inventive graft,with openings corresponding to the plurality of patterned recesses inthe graft material.

While the invention has been described with reference to its preferredembodiments, those of ordinary skill in the relevant arts willunderstand and appreciate that the present invention is not limited tothe recited preferred embodiments, but that various modifications inmaterial selection, deposition methodology, manner of controlling thematerial heterogeneities of the deposited stent material, and depositionprocess parameters may be employed without departing from the invention,which is to be limited only by the claims appended hereto.

What is claimed is:
 1. A method for controlling surface properties of animplantable medical device, comprising: a. vacuum depositing at leastone device forming metal selected from one of elemental nickel,elemental titanium, chromium-cobalt alloy, nickel-titanium alloy andnickel-titanium ternary alloy onto a cylindrical substrate maintained ata temperature range between about 300 to 1100 degrees Centigrade, toform a tubular device forming biomaterial on the cylindrical substrate;b. controlling the formation of heterogeneities at a blood or tissuecontacting surface of the tubular device forming biomaterial during thevacuum depositing step, such that controlled heterogeneities are formedat the blood or tissue contacting surface; and c. removing the formedbiomaterial from the substrate.
 2. The method according to claim 1,wherein the at least one device forming metal is selected the group ofbiocompatible metals consisting of elemental nickel, elemental titanium,tantalum, chromium-cobalt alloy, nickel-titanium alloy andnickel-titanium ternary alloy.
 3. The method according to claim 1,further comprising forming cell-adhesion domains having inter-domainboundaries less than the surface area of a human endothelial cell andwherein the substrate has a coefficient of thermal expansion differentthan that of the resultant implantable medical device.
 4. The methodaccording to claim 1, further comprising the step of definingcell-adhesion domains having inter-domain boundaries less than thesurface area of a human endothelial cell.
 5. The method according toclaim 1, wherein the controlled heterogeneities are dimensioned to havea blood contact surface area of about less than 6 μm2.
 6. The methodaccording to claim 1, wherein the controlled heterogeneities areselected from the group consisting of grain size, grain phase and graincomposition and luminal surface topography.
 7. The method according toclaim 1, wherein the controlled heterogeneities have a blood contactsurface of diameter less than or equal to about 10 μm and aninter-heterogeneity boundary between about 0 and 2 μm.
 8. The methodaccording to claim 1, wherein the controlled heterogeneities aredimensioned to have a blood contact surface area of about less than 6μm².
 9. The method according to claim 1, wherein the cylindricalsubstrate is maintained at a non-zero bias voltage present between about−1000 and +1000 volts applied to the generally cylindrical substratesufficient to impart a hyperthermal energy of energetic species arrivingat the surface of the substrate to between about 0.1 eV and about 700eV.
 10. A method for controlling surface properties of an implantablemedical device, comprising the steps of: a. forming a tubularnickel-titanium alloy biomaterial onto a substrate maintained at atemperature range between about 300 to 1100 degrees Centigrade andnon-zero bias voltage applied to the generally cylindrical substratesufficient to impart a hyperthermal energy of energetic species arrivingat the surface of the substrate to between about 0.1 eV and about 700eV, the substrate having a pre-determined pattern of topographicalfeatures on an exterior surface thereof, wherein the pattern oftopographical features comprises a positive or negative pattern that isimparted to the device forming biomaterial; b. controlling the formationof heterogeneities at a blood or tissue contacting surface of thebiomaterial by fabricating the bulk material of the medical device tohave a defined grain sizes that yield sites along the surface of themedical device having protein binding capability, wherein the controlledheterogeneities have a blood contact surface of diameter less than orequal to about 10 μm and an inter-heterogeneity boundary between about 0and 2 μm; and c. removing the medical device from the substrate.
 11. Themethod according to claim 10, wherein the nickel-titanium alloy is abinary or ternary alloy.
 12. The method according to claim 10, whereinthe step of controlling the formation of heterogeneities furthercomprises etching.
 13. The method according to claim 10 furthercomprising forming cell-adhesion domains having inter-domain boundariesless than the surface area of a human endothelial cell and wherein thesubstrate has a coefficient of thermal expansion different than that ofthe resultant medical device.
 14. The method according to claim 10,wherein the controlled heterogeneities are dimensioned to have a bloodcontact surface area of about less than 6 μm2.
 15. The method accordingto claim 10, wherein the controlled heterogeneities further include agrain phase and a grain composition.
 16. The method according to claim10, wherein the implantable medical device is a tubular device and thecontrolled heterogeneities are on the luminal surface topography.
 17. Amethod for controlling surface properties of an implantable medicaldevice, comprising: a. vacuum depositing a generally tubularnickel-titanium alloy device onto a substrate, the substrate having apre-determined pattern of recesses and the substrate is maintained at anon-zero bias voltage present between about −1000 and +1000 voltsapplied to the generally cylindrical substrate sufficient to impart ahyperthermal energy of energetic species arriving at the surface of thesubstrate to between about 0.1 eV and about 700 eV; b. controlling theformation of heterogeneities at a blood or tissue contacting surface ofthe biomaterial during fabrication of the medical device, such thatcontrolled heterogeneities are formed and have a substantiallyhomogeneous surface energy and electrostatic charge across a bloodcontact surface of the metal film, wherein the controlledheterogeneities have a blood contact surface of diameter less than orequal to about 10 μm and an inter-heterogeneity boundary between about 0and 2 μm; and c. removing the medical device from the substrate.
 18. Themethod according to claim 17, wherein the controlled heterogeneities areselected from the group consisting of grain size, grain phase and graincomposition and luminal surface topography.
 19. The method according toclaim 17, wherein the step of controlling the formation ofheterogeneities further comprises etching.
 20. The method according toclaim 17, wherein the controlled heterogeneities are materialcompositions.
 21. The method according to claim 17, wherein thesubstrate has a coefficient of thermal expansion different than that ofthe resultant medical device.
 22. The method according to claim 17,wherein the substrate is maintained at a temperature range between about300 to 1100 degrees Centigrade.
 23. The method according to claim 17,wherein the controlled heterogeneities are on the luminal surface.